Cardiac hypertrophy is the result of complex genetically predetermined electrical and mechanical remodeling[unreadable] programs in response to mechanical and neurohumoral stimuli. Ca plays a pivotal role in the activation and[unreadable] regulation of several hypertrophy transcription pathways, while Ca signaling itself undergoes profound[unreadable] changes in hypertrophy (Hyp) and heart failure (HF), including significant contributions from InsP3-dependent[unreadable] Ca release.[unreadable] The specific aims of the proposed study are:[unreadable] 1) characterize the role of InsP3-dependent Ca signaling for excitation-contraction coupling (ECC) in[unreadable] atrial and ventricular myocytes under physiological conditions and in Hyp/HF.[unreadable] 2) test the hypothesis that InsP3-dependent Ca release facilitates arrhythmogenic Ca signals (SR Ca[unreadable] overload, Ca waves, Ca alternans, enhanced Ca spark frequency) and changes of membrane potential[unreadable] (early (EAD) and delayed (DAD) afterdepolarizations, spontaneous action potentials (APs) and[unreadable] electrical alternans) in Hyp/HF ventricular myocytes.[unreadable] 3) identify the cellular and subcellular Ca signaling pathways and spatio-temporal [Ca], patterns[unreadable] relevant for nuclear Ca/calmodulin/calcineurin-dependent NFAT translocation which initiate gene[unreadable] transcription and gene expression in cardiac Hyp and HF.[unreadable] To achieve these aims a multitude of experimental techniques will be used: high resolution Ca imaging by[unreadable] laser scanning confocal microscopy in single cardiac myocytes, novel FRET(CFP/YFP) fluorescent InsP3[unreadable] sensors to study the cellular and subcellular dynamics of InsP3, whole-cell voltage clamp techniques to study[unreadable] membrane currents and membrane potential changes, and molecular biological and pharmacological tools to[unreadable] manipulate the InsP3/Ca/calmodulin/clacineurin/NFAT signaling cascade. Furthermore, several animal/cell[unreadable] models will be used including wild-type mouse and rabbit, hypertrophy mouse, InsPa receptor knockout[unreadable] mouse and heart failure rabbit.[unreadable] The proposed research will generate fundamental new information on the roles of InsP3R-dependent Ca[unreadable] signaling in cardiac myocytes during ECC, in arrhythmogenesis, electrophysiological changes and nuclear[unreadable] transcription signaling in normal, Hyp and HF cardiac myocytes.[unreadable]